GLP-1 Receptor Agonists Could Find Additional Role for Headache Relief

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Data from a phase 2 randomized clinical trial demonstrate use of the GLP-1 receptor agonist exenatide could be used as a treatment for idiopathic intracranial hypertension in women.

The next area of use for GLP-1 receptor agonists could be treatment of idiopathic intracranial hypertension, according to the results of a phase 2 study.

A randomized clinical trial of 15 women comparing use of eventide against placebo therapy, results of the study indicate use of the GLP-1 receptor agonist was associated with a statistically significant reduction in short- and long-term intracranial pressure, with results also indicating exenatide use was associated with a reduction in number of headache days per month.1

“We are delighted to see that the phase two trial resulted in our treatment group having lower brain pressure both immediately and after 12 weeks and nearly 8 fewer headache days across the 12-week period, and that all the women were able to continue the treatment throughout with few adverse effects,” said senior investigator Alexandra Sinclair, MBChB, PhD, professor of Neurology in the Institute of Metabolism and Systems Research at the University of Birmingham.2 “We now hope to see a much larger trial of exenatide to literally ease the pressure for the many people around the world suffering with idiopathic intracranial hypertension.”

Few classes have seen a revolution in use that has occurred for GLP-1 receptor agonists in recent years, with the agent’s role expanding from glycemic control to weight loss. Now, as their growing role in cardiometabolic role continues to blossom, the current study offers new insight into the effects on idiopathic intracranial hypertension.

Led by a team of neurologists from the University of Birmingham and University Hospitals Birmingham, the phase 2 randomized clinical trial was launched with the intent of comparing use of eventide against placebo therapy among adult women with active idiopathic intracranial hypertension, which was defined as an intracranial pressure greater than 25 cmCSF and papilloedema. Investigators designed their study with 3 primary outcomes of interest, which included intracranial pressure at 2.5 hours, 24 hours, and 12 weeks and alpha set α priori at less than 0.1.1

From November 1, 2017-September 17, 2018, a total of 16 patients underwent enrollment and 15 were randomly assigned to eventide (n=7) or placebo therapy (n=8). Investigators noted the patient who underwent enrollment but not randomization withdrew as a result of requiring urgent CSF shunting. Investigators also noted age, BMI, andintracranial pressure at baseline was well-matched between the study groups.1

Upon analysis, results indicated the mean difference in intracranial pressure was -4.2 (SD 2.1; P=.048) mmHg at 2.5 hours, -4.7 (SD, 2.1; P=.030) mmHg at 24 hours, and -4.1 (SD, 2.2; P=.058). Investigators pointed out these changes were equivalent to reductions of 5.7 (SD, 2.9), 6.4 (SD, 2.9), and 5.6 (SD 3.9) cmCSF at 2.5 hours, 24 hours, and 12 weeks, respectively. Analysis of secondary outcomes of interest indicated the monthly headache days were reduced in the exenatide arm relative to placebo therapy (-7.7 [SD, 9.2] vs -1.5 [SD, 4.8] days; P=.404), but no significant difference was observed between the study arms at 12 weeks.1

Further analysis of secondary outcomes suggested there were no significant changes in intraocular pressure or quality of life between the study arms, but visual acuity was significantly improved in the exenatide arm (-0.1 [SD, 0.05] logMar units; P =.036). When assessing safety outcomes results indicated 12 adverse events were reported during the trial, with 8 occurring in the exenatide arm. Of these 8, investigators underlined 7 were caused related to exenatide initiation.1

“The results of this clinical trial are a shot in the arm for finding clinical treatments for [idiopathic intracranial hypertension],” said lead investigator James Mitchell, Lecturer in Neurology at the University of Birmingham.2 “While we need to do further trials before such a treatment could be available for patients in the future, we are encouraged by the significant results from this trial that made a real difference for those in the treatment arm and this treatment may prove relevant for other conditions resulting in raised brain pressure.”


  1. James L Mitchell, Hannah S Lyons, Jessica K Walker, et al. The effect of GLP-1RA exenatide on idiopathic intracranial hypertension: a randomized clinical trial, Brain, 2023;, awad003,
  2. New Drug to lower brain pressure could treat blinding IIH headaches, trial finds. EurekAlert! Published March 12, 2023. Accessed March 14, 2023.